Melatonin is a multifunctional indole hormone mainly secreted by the pineal gland in mammals. It has been known that melatonin, as an antioxidant, regulates sleep and circadian rhythms, enhances immunity, suppresses tumors, and delays aging process of mammals. This review summarized the mechanisms by which melatonin plays its function in delaying aging in mammals from two aspects of oxidative stress and energy metabolism, including retarding oxidative stress by scavenging free radicals, stimulating antioxidation and protecting mitochondrial function, and regulating energy metabolism by modulating metabolic sensing, re-establishing circadian rhythm and promoting energy expenditure. Finally, the future development of this field is prospected.